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By
Dr. Rola Makhoul-Farah
PharmD, MSc, MHA
2012
DRUGS USED IN ACIDPEPTIC DISEASES
Acid-peptic diseases




gastroesophageal reflux
peptic ulcer (gastric and duodenal)
stress-related mucosal injury
In these situations : Mucosal erosions or ulceration arise when the
caustic effects of aggressive factors (acid, pepsin, bile) overwhelm
the defensive factors of the gastrointestinal mucosa (mucus and
bicarbonate secretion, prostaglandins, blood flow, and the
processes of restitution and regeneration after cellular injury
Over 90% of peptic ulcers are caused by :

infection with the bacterium Helicobacter
pylori
or by

use of nonsteroidal anti-inflammatory
drugs (NSAIDs)
Drugs used in the treatment of acid-peptic
disorders may be divided into two classes:
1. agents that reduce intragastric acidity
2. agents that promote mucosal defense
ANTACIDS
Used for:

Dyspepsia

Intermittent heartburn

Antacids are weak bases that react with
gastric hydrochloric acid to form a salt and
water

Their principal mechanism of action is
reduction of intragastric acidity
Sodium bicarbonate

eg, baking soda, Alka Seltzer

reacts rapidly with hydrochloric acid (HCL) to produce
carbon dioxide and sodium chloride

Formation of carbon dioxide results in gastric distention
and belching

Unreacted alkali is readily absorbed, potentially causing metabolic
alkalosis when given in high doses or to patients with renal
insufficiency

Sodium chloride absorption may exacerbate fluid retention in
patients with heart failure, hypertension, and renal insufficiency
Calcium carbonate



eg, Tums
is less soluble and reacts more slowly than sodium
bicarbonate with HCl to form carbon dioxide and calcium
chloride (CaCl2)
Like sodium bicarbonate, calcium carbonate may cause
belching or metabolic alkalosis
magnesium hydroxide or aluminum hydroxide

eg, Maalox
react slowly with HCl to form magnesium chloride or aluminum
chloride and water

Because no gas is generated, belching does not occur.

Metabolic alkalosis is also uncommon because of the efficiency of
the neutralization reaction

Unabsorbed magnesium salts may cause an osmotic diarrhea
Aluminum salts may cause constipation



Patients with renal insufficiency should not take these agents longterm
All antacids may affect the absorption of other
medications by:

binding the drug (reducing its absorption)

increasing intragastric pH so that the drug's dissolution
or solubility (especially weakly basic or acidic drugs) is
altered
Therefore, antacids should not be given within
2 hours of doses of tetracyclines,
fluoroquinolones, itraconazole, and iron.
H2- antagonist
Four H2 antagonists are in clinical use:
 cimetidine, ranitidine, famotidine, and nizatidine



All four agents are rapidly absorbed from the intestine
Cimetidine, ranitidine, and famotidine undergo first-pass
hepatic metabolism resulting in a bioavailability of
approximately 50%
The serum half-lives of the four agents range from 1.1 to
4 hours; however, duration of action depends on the
dose given
Table 62–1 Clinical Comparisons of H2-Receptor Blockers.
Drug
Relative
Dose to
Usual Dose
Usual Dose for
Usual Dose for
Potency
Achieve >
for Acute
Gastroesophageal
Prevention of
50% Acid
Duodenal or
Reflux Disease
Stress-Related
Inhibition for
Gastric Ulcer
Bleeding
10 Hours
C imetidine 1
400–800 mg
800 mg HS or
800 mg bid
400 mg bid
50 mg/h
continuous
infusion
Ranitidine
4–10
150 mg
300 mg HS or
150 mg bid
150 mg bid
6.25 mg/h
continuous
infusion or 50 mg
IV every 6–8 h
Nizatidine
4–10
150 mg
300 mg HS or
150 mg bid
Not available
20 mg bid
20 mg IV every
150 mg bid
Famotidine 20–50
20 mg
40 mg HS or
20 mg bid
BID, twice daily; HS, bedtime.
12 h
H2 antagonists reduce acid secretion stimulated by
histamine as well as by gastrin and cholinomimetic
agents through two mechanisms:

First, histamine released from ECL cells by
gastrin or vagal stimulation is blocked from
binding to the parietal cell H2 receptor

Second, direct stimulation of the parietal cell by
gastrin or acetylcholine has a diminished effect
on acid secretion in the presence of H2-receptor
blockade

H2 antagonists are especially effective at inhibiting
nocturnal acid secretion (which depends largely on
histamine)

Recommended prescription doses maintain greater than
50% acid inhibition for 10 hours; hence, these drugs are
commonly given twice daily

At doses available in over-the-counter formulations, the
duration of acid inhibition is less than 6 hours
GASTROESOPHAGEAL REFLUX DISEASE (GERD)

Patients with infrequent heartburn or dyspepsia (fewer than 3 times
per week) may take either antacids or intermittent H2 antagonists

Because antacids provide rapid acid neutralization, they afford faster
symptom relief than H2 antagonists

H2 antagonists may be taken prophylactically before meals in an
effort to reduce the likelihood of heartburn

Frequent heartburn is better treated with twice-daily H2 antagonists
or proton pump inhibitors

In patients with erosive esophagitis (approximately 50% of patients
with GERD), H2 antagonists afford healing in less than 50% of
patients; hence proton pump inhibitors are preferred because of
their superior acid inhibition.
PREVENTION OF BLEEDING FROM STRESS-RELATED GASTRITIS

Clinically important bleeding from upper gastrointestinal erosions or ulcers
occurs in 1–5% of critically ill patients as a result of impaired mucosal
defense mechanisms caused by poor perfusion

Although most critically ill patients have normal or decreased acid secretion,
numerous studies have shown that agents that increase intragastric pH (H2
antagonists or proton pump inhibitors) reduce the incidence of clinically
significant bleeding

However, the optimal agent is uncertain at this time

For patients without a nasoenteric tube or with significant ileus, intravenous
H2 antagonists are preferable over intravenous proton pump inhibitors
because of their proven efficacy and lower cost

Continuous infusions of H2 antagonists are generally preferred to bolus
infusions because they achieve more consistent, sustained elevation of
intragastric pH.
Table 62–2 Pharmacokinetics of Proton Pump Inhibitors.
Drug
pK a Bioavailability
(%)
t1/2
(h)
Tmax
(h)
Usual Dosage for
Peptic Ulcer or
GERD
Omeprazole
4
Esomeprazole 4
40–65
0.5–
1.5
1–3.5 20–40 mg qd
> 80
1.2–
1.6
20–40 mg qd
1.5
1.7
30 mg qd
1.5
Lansoprazole 4
> 80
Pantoprazole
3.9 77
1.0–
1.9
2.5–
4.0
40 mg qd
Rabeprazole
5
1.0–
2.0–
20 mg qd
2.0
5.0
52
GERD, gastroesophageal reflux disease.

Proton pump inhibitors are administered as inactive prodrugs

To protect the acid-labile prodrug from rapid destruction within the
gastric lumen, oral products are formulated for delayed release as
acid-resistant, enteric-coated capsules or tablets

After passing through the stomach into the alkaline intestinal lumen,
the enteric coatings dissolve and the prodrug is absorbed

For children or patients with dysphagia or enteral feeding tubes,
capsules may be opened and the microgranules mixed with apple or
orange juice or mixed with soft foods (eg, applesauce).
H pylori-Associated Ulcers
The best treatment regimen consists of a 14-day regimen
of "triple therapy":
 a proton pump inhibitor twice daily;
 clarithromycin, 500 mg twice daily;
 and either amoxicillin, 1 g twice daily, or metronidazole,
500 mg twice daily.

After completion of triple therapy, the proton pump
inhibitor should be continued once daily for a total of 4–6
weeks to ensure complete ulcer healing.
NSAID-Associated Ulcers



either H2 antagonists or proton pump inhibitors
provide rapid ulcer healing so long as the NSAID
is discontinued;
however continued use of the NSAID impairs
ulcer healing.
In patients with NSAID-induced ulcers who
require continued NSAID therapy, treatment with
a once- or twice-daily proton pump inhibitor
more reliably promotes ulcer healing
BISMUTH COMPOUNDS

Bismuth coats ulcers and erosions, creating a protective
layer against acid and pepsin.

It may also stimulate prostaglandin, mucus, and
bicarbonate secretion.

Bismuth subsalicylate reduces stool frequency and
liquidity in acute infectious diarrhea.

Bismuth has direct antimicrobial effects and binds
enterotoxins, accounting for its benefit in preventing and
treating traveler's diarrhea.
Bismuth compounds have direct antimicrobial activity
against H pylori.

Bismuth subsalicylate
(Kalbeten, pink-Bismuth, Pepto-Bismol)

is used for the prevention of traveler's
diarrhea (30 mL or 2 tablets four times
daily).

Bismuth compounds are used in 4 drug regimen
for the eradication of H pylori infection


a proton pump inhibitor twice daily
bismuth subsalicylate (2 tablets; 262 mg each)
tetracycline (250–500 mg)
metronidazole (500 mg) four times daily

for 10–14 days


DRUGS STIMULATING
GASTROINTESTINAL
MOTILITY
Drugs that can selectively stimulate gut motor function
(prokinetic agents) have significant potential clinical
usefulness.
 Agents that increase lower esophageal sphincter
pressures may be useful for GERD

Drugs that improve gastric emptying may be helpful for
gastroparesis and postsurgical gastric emptying delay

Agents that stimulate the small intestine may be
beneficial for postoperative ileus or chronic intestinal
pseudo-obstruction

Agents that enhance colonic transit may be useful in the
treatment of constipation
CHOLINOMIMETIC AGENTS

Cholinomimetic agonists such as bethanechol stimulate
muscarinic M3 receptors on muscle cells and at
myenteric plexus synapses

Bethanechol was used in the past for the treatment of
GERD and gastroparesis

Owing to multiple cholinergic effects and the advent of
less toxic agents, it is now seldom used.

The acetylcholinesterase inhibitor neostigmine can
enhance gastric, small intestine, and colonic emptying

Intravenous neostigmine has enjoyed a resurgence in
clinical usage for the treatment of hospitalized patients
with acute large bowel distention

Administration of 2 mg results in prompt colonic
evacuation of flatus and feces in the majority of patients

Cholinergic effects include excessive salivation, nausea,
vomiting, diarrhea, and bradycardia.
METOCLOPRAMIDE & DOMPERIDONE

They are dopamine D2 receptor antagonists

Within the gastrointestinal tract activation of dopamine receptors
inhibits cholinergic smooth muscle stimulation; blockade of this
effect is believed to be the primary prokinetic mechanism of
action of these agents.

These agents increase esophageal peristaltic amplitude,
increase lower esophageal sphincter pressure, and enhance
gastric emptying


but have no effect on small intestine or colonic motility
Metoclopramide and domperidone also block dopamine D2
receptors in the chemoreceptor trigger zone of the medulla (area
postrema), resulting in potent antinausea and antiemetic action
The most common adverse effects of metoclopramide
involve the central nervous system:

Restlessness, drowsiness, insomnia, anxiety, and agitation occur in
10–20% of patients, especially the elderly

Extrapyramidal effects (dystonias, akathisia, parkinsonian features)
due to central dopamine receptor blockade

Elevated prolactin levels (caused by both metoclopramide and
domperidone) can cause galactorrhea, gynecomastia, impotence,
and menstrual disorders
 Domperidone
is extremely well
tolerated
 Because
it does not cross the bloodbrain barrier to a significant degree,
neuropsychiatric and extrapyramidal
effects are rare.
MACROLIDES

Macrolide antibiotics such as erythromycin directly
stimulate motilin receptors on gastrointestinal smooth
muscle and promote the onset of a migrating motor
complex

Intravenous erythromycin (3 mg/kg) is beneficial in some
patients with gastroparesis; however, tolerance rapidly
develops

It may be used in patients with acute upper
gastrointestinal hemorrhage to promote gastric emptying
of blood before endoscopy
LAXATIVES
BULK-FORMING LAXATIVES:

Bulk-forming laxatives are indigestible, hydrophilic colloids that
absorb water, forming a bulky, emollient gel that distends the colon
and promotes peristalsis.

Common preparations include natural plant products (psyllium,
methylcellulose) and synthetic fibers (polycarbophil)

Bacterial digestion of plant fibers within the colon may lead to
increased bloating and flatus.
STOOL SURFACTANT AGENTS (SOFTENERS):

These agents soften stool material, permitting water and lipids to
penetrate.

They may be administered orally or rectally.

Common agents include docusate(oral or enema) and glycerin
suppository.
SOFTENERS:
Mineral oil

is a clear, viscous oil that lubricates fecal material, retarding water
absorption from the stool

It is used to prevent and treat fecal impaction in young children and
debilitated adults

It is not palatable but may be mixed with juices

Aspiration can result in a severe lipid pneumonitis

Long-term use can impair absorption of fat-soluble vitamins (A, D, E, K).
OSMOTIC LAXATIVES

The colon can neither concentrate nor dilute fecal fluid:
fecal water is isotonic throughout the colon

Osmotic laxatives are soluble but nonabsorbable
compounds that result in increased stool liquidity due to
an obligate increase in fecal fluid
Magnesium hydroxide (milk of magnesia)
Sorbitol
Lactulose



Osmotic laxative

The most commonly used purgatives are magnesium
citrate and sodium phosphate

High doses of osmotically active agents produce prompt
bowel evacuation (purgation) within 1–3 hours

The rapid movement of water into the distal small bowel
and colon leads to a high volume of liquid stool followed
by rapid relief of constipation.
Osmotic laxative
Balanced Polyethylene Glycol

These balanced, isotonic solutions contain an inert,
nonabsorbable, osmotically active sugar (PEG) with
sodium sulfate, sodium chloride, sodium bicarbonate,
and potassium chloride.

The solution is designed so that no significant
intravascular fluid or electrolyte shifts occur.

Therefore, they are safe for all patients.

The solution should be ingested rapidly (2–4 L over 2–4
hours) to promote bowel cleansing.

For treatment or prevention of chronic
constipation, smaller doses of PEG
powder may be mixed with water or
juices (17 g/8 oz) and ingested daily.

In contrast to sorbitol or lactulose, PEG
does not produce significant cramps or
flatus.
STIMULANT LAXATIVES

Direct stimulation of the enteric nervous system and
colonic electrolyte and fluid secretion

There has been concern that long-term use of cathartics
could lead to dependence and destruction of the
myenteric plexus, resulting in colonic atony and dilation

More recent research suggests that long-term use of
these agents probably is safe in most patients

Cathartics may be required on a long-term basis,
especially in patients who are neurologically impaired
and in bed-bound patients in long-term care
facilities.
Anthraquinone Derivatives

Aloe, senna, and cascara (plants)

Chronic use leads to a characteristic brown
pigmentation of the colon known as "melanosis
coli."

There has been some concern that these agents
may be carcinogenic, but epidemiologic studies
do not suggest a relation to colorectal cancer
Diphenylmethane Derivatives

Bisacodyl is available in tablet and suppository
formulations for the treatment of acute and chronic
constipation

It also is used in conjunction with PEG solutions for
colonic cleansing prior to colonoscopy

Phenolphthalein, another agent in this class, was
removed from the market owing to concerns about
possible cardiac toxicity.
ANTIDIARRHEAL AGENTS
OPIOID AGONISTS:
 Opioids have significant constipating effects

They increase colonic phasic segmenting activity through inhibition
of presynaptic cholinergic nerves in the submucosal and myenteric
plexuses and lead to increased colonic transit time and fecal water
absorption

They also decrease mass colonic movements and the gastrocolic
reflex

Although all opioids have antidiarrheal effects, central
nervous system effects and potential for addiction limit
the usefulness of most
Loperamide:

Is a nonprescription opioid agonist
does not cross the blood-brain barrier
has no analgesic properties or potential for addiction

Tolerance to long-term use has not been reported

It is typically administered in doses of 2 mg taken one to
four times daily


5-HT3 antagonists

are a class of medications that act as receptor
antagonists at the 5-HT3 receptor, a subtype of serotonin
receptor found in terminals of the vagus nerve and in
certain areas of the brain

Almost all 5-HT3 antagonists are antiemetics, used in the
prevention and treatment of nausea and vomiting

They are particularly effective in controlling the nausea
and vomiting produced by cancer chemotherapy and are
considered the gold standard for this purpose
Comparative pharmacology of 5-HT3 receptor antagonist[10]
Drug
Chemical
nature
Receptor
antagonists
T1/2 (h)
Metabolism
Carbazole
Ondansetron
derivative
5-HT3
receptor
antagonist
and weak 5HT4
antagonist
3.9 hours
CYP1A1/2,
CYP2D6,
0.15 mg/kg
CYP 3A3/4/5
Granisetron
5-HT3
receptor
antagonist
9-11.6 hours
CYP3A3/4/5
Indazole
Dose
10 µg/kg
CORTICOSTEROIDS

Corticosteroids (dexamethasone, methylprednisolone)
have antiemetic properties, but the basis for these
effects is unknown

These agents appear to enhance the efficacy of 5-HT3receptor antagonists for prevention of acute and delayed
nausea and vomiting in patients receiving moderately to
highly emetogenic chemotherapy regimens

Although a number of corticosteroids have been used,
dexamethasone, 8–20 mg intravenously before
chemotherapy, followed by 8 mg/d orally for 2–4 days, is
commonly administered.
NEUROKININ RECEPTOR ANTAGONISTS

Neurokinin 1 (NK1)-receptor antagonists have antiemetic
properties that are mediated through central blockade in
the area postrema

Aprepitant (an oral formulation) is a highly selective
NK1-receptor antagonist that crosses the blood-brain
barrier and occupies brain NK1 receptors

It has no affinity for serotonin, dopamine, or
corticosteroid receptors

Fosaprepitant is an intravenous formulation that is
converted within 30 minutes after infusion to aprepitant
PHENOTHIAZINES & BUTYROPHENONES

Phenothiazines are antipsychotic agents that can be
used for their potent antiemetic and sedative properties

The antiemetic properties of phenothiazines are
mediated through inhibition of dopamine and muscarinic
receptors

Sedative properties are due to their antihistamine activity

The agents most commonly used as antiemetics are
prochlorperazine, promethazine, and
thiethylperazine.

Antipsychotic butyrophenones also
possess antiemetic properties due to their
central dopaminergic blockade
The main agent used is droperidol, which
can be given by intramuscular or
intravenous injection
 In antiemetic doses, droperidol is
extremely sedating.

H1 ANTIHISTAMINES &
ANTICHOLINERGIC DRUGS

As single agents, these drugs have weak antiemetic activity, although they
are particularly useful for the prevention or treatment of motion sickness.

Their use may be limited by dizziness, sedation, confusion, dry mouth,
cycloplegia, and urinary retention.

Diphenhydramine and one of its salts, dimenhydrinate, are firstgeneration histamine H1 antagonists that also have significant
anticholinergic properties

Because of its sedating properties, diphenhydramine is commonly used in
conjunction with other antiemetics for treatment of emesis due to
chemotherapy